Targeting and Modulation of the Natriuretic Peptide System in Covid-19: A Single or Double-Edged Effect?

Natriuretic peptide system (NPS) is a group of peptide hormones or paracrine factors, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and natriuretic peptide precursor C (NPC), that are structurally related. The physiological effects of NPS include natriuresis, increased glomerular filtration rate, inhibition release of renin, vasopressin, and aldosterone, sympathetic inhibition, vasodilatations, and prevents cardiac hypertrophy and remodeling. ANP has immunological effects, as it is produced locally from immune cells; it regulates innate and adaptive immune responses. Metabolism and degradation of ANP are achieved by neutral endopeptidase (NEP), also known as neprilysin. Coronavirus disease 2019 (Covid-19) pandemic may lead to acute lung injury (ALI) and/or respiratory distress syndrome (ARDS). The underlying causes of inflammatory and immunological disorders in patients with severe Covid-19 are connected to the immune over-stimulation with the subsequent release of pro-inflammatory cytokines. Covid-19 severity is linked with high ANP serum levels regardless of acute cardiac injury. Inflammatory stimuli appear to be linked with the release of NPs, which anti-inflammatory effects prevent the development of ALI/ARDS in Covid-19. Therefore, neprilysin inhibitors like sacubitril increase endogenous NPs and may reduce the risk of ALI in Covid-19 due to the potentiation of endogenous anti-inflammatory effects of NPs. However, sacubitril increases gastrin-releasing peptide, cathepsin G and release of pro-inflammatory cytokines that are inactivated by neprilysin. In conclusion, NPs and neprilysin have cardio-pulmonary protective effects against Covid-19-induced ALI/ARDS. Neprilysin inhibitor sacubitril has dual protective and harmful effects regarding metabolizing vasoactive peptides by neprilysin. These findings require potential reevaluation of the effect of neprilysin inhibitors in managing Covid-19.

New therapies for the treatment of heart failure with preserved ejection fraction.

PURPOSE: This review of chronic heart failure with preserved ejection fraction (HFpEF), including new and emerging evidence for treatment of patients with this condition, is intended to offer data supporting the use of specific agents for this patient population. SUMMARY: Chronic heart failure is a major health concern affecting millions of Americans annually and remains a significant burden on the healthcare system. Heart failure is divided into categories based on left ventricular ejection fraction (LVEF). Current treatments for heart failure with reduced ejection fraction, defined by an LVEF of less than 40%, involve a variety of agents with established morbidity and mortality benefits. This is in stark contrast to directed treatments for patients with HFpEF, defined by an LVEF of greater than 50%. Treatments for this form of heart failure have been elusive until recently, when studies were published with sacubitril/valsartan and empagliflozin. Results of the PARAGON-HF trial suggested benefit from sacubitril/valsartan in patients with an ejection fraction between 45% and 57%, leading to its approval in 2021 as the first medication indicated for treatment of patients with a preserved ejection fraction. Months later, the results of the EMPEROR-Preserved trial demonstrated a statistically significant benefit in the composite outcome of heart failure hospitalizations and cardiovascular death in patients with HFpEF taking empagliflozin. This medication has yet to gain approval for HFpEF; however, these data along with ongoing and future trials will likely impact standard treatment for these patients. CONCLUSION: The PARAGON-HF and EMPEROR-Preserved trials will serve as the foundation for a new era in the treatment of HFpEF.

Advances in Clinical Cardiology 2021: A Summary of Key Clinical Trials.

INTRODUCTION: Over the course of 2021, numerous key clinical trials with valuable contributions to clinical cardiology were published or presented at major international conferences. This review seeks to summarise these trials and reflect on their clinical context. METHODS: The authors reviewed clinical trials presented at major cardiology conferences during 2021 including the American College of Cardiology (ACC), European Association for Percutaneous Cardiovascular Interventions (EuroPCR), European Society of Cardiology (ESC), Transcatheter Cardiovascular Therapeutics (TCT), American Heart Association (AHA), European Heart Rhythm Association (EHRA), Society for Cardiovascular Angiography and Interventions (SCAI), TVT-The Heart Summit (TVT) and Cardiovascular Research Technologies (CRT). Trials with a broad relevance to the cardiology community and those with potential to change current practice were included. RESULTS: A total of 150 key cardiology clinical trials were identified for inclusion. Interventional cardiology data included trials evaluating the use of new generation novel stent technology and new intravascular physiology strategies such as quantitative flow ratio (QFR) to guide revascularisation in stable and unstable coronary artery disease. New trials in acute coronary syndromes focused on shock, out of hospital cardiac arrest (OOHCA), the impact of COVID-19 on ST-elevation myocardial infarction (STEMI) networks and optimal duration/type of antiplatelet treatment. Structural intervention trials included latest data on transcatheter aortic valve replacement (TAVR) and mitral, tricuspid and pulmonary valve interventions. Heart failure data included trials with sodium-glucose cotransporter 2 (SGLT2) inhibitors, sacubitril/valsartan and novel drugs such as mavacamten for hypertrophic cardiomyopathy (HCM). Prevention trials included new data on proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. In electrophysiology, new data regarding atrial fibrillation (AF) screening and new evidence for rhythm vs. rate control strategies were evaluated. CONCLUSION: This article presents a summary of key clinical cardiology trials published and presented during the past year and should be of interest to both practising clinicians and researchers.

Impact of the COVID-19 pandemic on prescription of sacubitril/valsartan in Italy.

AIMS: The present study sought to examine the effect of the COVID-19 pandemic and lockdown measures on the prescription of sacubitril/valsartan in patients with heart failure (HF) in Italy. METHODS AND RESULTS: Data from Italian Medicines Agency (AIFA) monitoring registries were analysed. The sacubitril/valsartan monitoring registry is based on 6-month prescriptions. A monthly aggregation on new activations throughout the observational period was computed. From March to December 2020, the initiation of new HF patients on sacubitril/valsartan decreased by nearly 40% with prescriptions dropping to values similar to 2018 when the registry was still operated off-line. A slight increase in prescriptions was observed after the lockdown measures were lifted, but prescriptions remained constantly below the pre-lockdown period. CONCLUSION: A marked and worrisome decline during the COVID-19 pandemic in the activation of a life-saving treatment such as sacubitril/valsartan was observed. This decline was clearly linked to the lockdown measures instated to counteract the COVID-19 pandemic. Upcoming studies should analyse the occurrence of new cases of HF as well as the severity of patients admitted to hospitals and their mortality compared to pre-pandemic levels.

The year in cardiovascular medicine 2021: heart failure and cardiomyopathies.

In the year 2021, the universal definition and classification of heart failure (HF) was published that defines HF as a clinical syndrome with symptoms and/or signs caused by a cardiac abnormality and corroborated by elevated natriuretic peptide levels or objective evidence of cardiogenic congestion. This definition and the classification of HF with reduced ejection fraction (HFrEF), mildly reduced, and HF with preserved ejection fraction (HFpEF) is consistent with the 2021 ESC Guidelines on HF. Among several other new recommendations, these guidelines give a Class I indication for the use of the sodium-glucose co-transporter 2 (SGLT2) inhibitors dapagliflozin and empagliflozin in HFrEF patients. As the first evidence-based treatment for HFpEF, in the EMPEROR-Preserved trial, empagliflozin reduced the composite endpoint of cardiovascular death and HF hospitalizations. Several reports in 2021 have provided novel and detailed analyses of device and medical therapy in HF, especially regarding sacubitril/valsartan, SGLT2 inhibitors, mineralocorticoid receptor antagonists, ferric carboxymaltose, soluble guanylate cyclase activators, and cardiac myosin activators. In patients hospitalized with COVID-19, acute HF and myocardial injury is quite frequent, whereas myocarditis and long-term damage to the heart are rather uncommon.

Angiotensin Receptor-Neprilysin Inhibition in Acute Myocardial Infarction.

BACKGROUND: In patients with symptomatic heart failure, sacubitril-valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting-enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking. METHODS: We randomly assigned patients with myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril-valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to recommended therapy. The primary outcome was death from cardiovascular causes or incident heart failure (outpatient symptomatic heart failure or heart failure leading to hospitalization), whichever occurred first. RESULTS: A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril-valsartan and 2831 to receive ramipril. Over a median of 22 months, a primary-outcome event occurred in 338 patients (11.9%) in the sacubitril-valsartan group and in 373 patients (13.2%) in the ramipril group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P = 0.17). Death from cardiovascular causes or hospitalization for heart failure occurred in 308 patients (10.9%) in the sacubitril-valsartan group and in 335 patients (11.8%) in the ramipril group (hazard ratio, 0.91; 95% CI, 0.78 to 1.07); death from cardiovascular causes in 168 (5.9%) and 191 (6.7%), respectively (hazard ratio, 0.87; 95% CI, 0.71 to 1.08); and death from any cause in 213 (7.5%) and 242 (8.5%), respectively (hazard ratio, 0.88; 95% CI, 0.73 to 1.05). Treatment was discontinued because of an adverse event in 357 patients (12.6%) in the sacubitril-valsartan group and 379 patients (13.4%) in the ramipril group. CONCLUSIONS: Sacubitril-valsartan was not associated with a significantly lower incidence of death from cardiovascular causes or incident heart failure than ramipril among patients with acute myocardial infarction. (Funded by Novartis; PARADISE-MI ClinicalTrials.gov number, NCT02924727.).

Effect of Treatment With Sacubitril/Valsartan in Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial.

Importance: The use of sacubitril/valsartan is not endorsed by practice guidelines for use in patients with New York Heart Association class IV heart failure with a reduced ejection fraction because of limited clinical experience in this population. Objective: To compare treatment with sacubitril/valsartan treatment with valsartan in patients with advanced heart failure and a reduced ejection fraction and recent New York Heart Association class IV symptoms. Design, Setting, and Participants: A double-blind randomized clinical trial was conducted; a total of 335 patients with advanced heart failure were included. The trial began on March 2, 2017, and was stopped early on March 23, 2020, owing to COVID-19 risk. Intervention: Patients were randomized to receive sacubitril/valsartan (target dose, 200 mg twice daily) or valsartan (target dose, 160 mg twice daily) in addition to recommended therapy. Main Outcomes and Measures: The area under the curve (AUC) for the ratio of N-terminal pro-brain natriuretic peptide (NT-proBNP) compared with baseline measured through 24 weeks of therapy. Results: Of the 335 patients included in the analysis, 245 were men (73%); mean (SD) age was 59.4 (13.5) years. Seventy-two eligible patients (18%) were not able to tolerate sacubitril/valsartan, 100 mg/d, during the short run-in period, and 49 patients (29%) discontinued sacubitril/valsartan during the 24 weeks of the trial. The median NT-proBNP AUC for the valsartan treatment arm (n = 168) was 1.19 (IQR, 0.91-1.64), whereas the AUC for the sacubitril/valsartan treatment arm (n = 167) was 1.08 (IQR, 0.75-1.60). The estimated ratio of change in the NT-proBNP AUC was 0.95 (95% CI 0.84-1.08; P = .45). Compared with valsartan, treatment with sacubitril/valsartan did not improve the clinical composite of number of days alive, out of hospital, and free from heart failure events. Aside from a statistically significant increase in non-life-threatening hyperkalemia in the sacubitril/valsartan arm (28 [17%] vs 15 [9%]; P = .04), there were no observed safety concerns. Conclusions and Relevance: The findings of this trial showed that, in patients with chronic advanced heart failure with a reduced ejection fraction, there was no statistically significant difference between sacubitril/valsartan and valsartan with respect to reducing NT-proBNP levels. Trial Registration: ClinicalTrials.gov Identifier: NCT02816736.

Cost-Utility Analysis of Sacubitril-Valsartan Compared with Enalapril Treatment in Patients with Acute Decompensated Heart Failure in Thailand.

BACKGROUND: Sacubitril-valsartan is effective in reducing the N-terminal pro-B-type natriuretic peptide level of hospitalized patients with acute decompensated heart failure, with a high acquisition cost compared with enalapril treatment. OBJECTIVE: This study aimed to determine the cost utility of sacubitril-valsartan compared with enalapril for acute decompensated heart failure treatment. METHODS: A Markov model was constructed to project the total costs, life-years, quality-adjusted life-years (QALYs) of early initiation, and a 2-month delay of sacubitril-valsartan treatment and enalapril treatment in hospitalized patients with acute decompensated heart failure over a lifetime horizon from a Thai healthcare system perspective. Clinical inputs were mainly derived from the PIONEER-HF and PARADIGM-HF trials, together with Thai epidemiological data. Cost data were based on the Thai population. All costs and outcomes were discounted at 3% annually. A series of sensitivity analyses were performed. RESULTS: Compared with enalapril, sacubitril-valsartan incurred a higher total cost per year (THB 42,994 [US$1367.48] vs THB 19,787 [US$629.37]), and it gained more QALYs (4.969 vs 4.755). The incremental cost-effectiveness ratio was THB 108,508/QALY (US$3451.26/QALY). Early initiation of sacubitril-valsartan treatment was more cost effective than delayed treatment. Sensitivity analyses revealed that at a level of willingness to pay of THB 160,000/QALY (US$5089/QALY), sacubitril-valsartan was a cost-effective strategy of about 60%. CONCLUSIONS: Sacubitril-valsartan is cost effective in patients with acute decompensated heart failure. However, the results are highly dependent on the long-term cardiovascular mortality, and they are applicable only to Thailand or countries with a similarly structured healthcare system. Long-term registries should be pursued to decrease the uncertainty around long-term mortality.

[ANMCO Position paper: Use of sacubitril/valsartan in hospitalized patients with acute heart failure]. / Position paper ANMCO: Utilizzo di sacubitril/valsartan nel paziente ricoverato con scompenso cardiaco acuto.

Sacubitril/valsartan (S/V) has been shown to reduce the risk of cardiovascular death or heart failure hospitalization and improve symptoms in chronic heart failure with reduced ejection fraction compared to enalapril. After 7 years since the publication of the results of PARADIGM-HF, further insight has been gained with potential new indications. Two prospective randomized multicenter studies (PIONEER-HF and TRANSITION) in patients hospitalized for acute heart failure (AHF) have shown an improved clinical outcome and biomarker profile as compared to enalapril, and good tolerability, safety and feasibility of initiating in-hospital administration of S/V. Furthermore, some studies have highlighted the favorable effects of S/V in attenuating adverse myocardial remodeling, supporting an early benefit after treatment. Observational data from non-randomized studies in AHF report that in-hospital and pre-discharge prescription of evidence-based drugs associated with better survival still remains suboptimal. Additionally, the COVID-19 pandemic has also negatively impacted on outpatient activities. Therefore, hospitalization, a real crossroads in the history of heart failure, must become a management and therapeutic opportunity for our patients. The objective of this ANMCO position paper is to encourage and facilitate early S/V administration in stabilized patients during hospitalization after an AHF episode, with the aim of improving care efficiency and clinical outcome.

Scientific hypothesis and rational pharmacological for the use of sacubitril/valsartan in cardiac damage caused by COVID-19.

On March 11, 2020 the World Health Organization (WHO) declared the state of global pandemic caused by the new SARS-CoV-2 (COVID-19). To date, no antivirals directed against SARS-CoV-2 or effective vaccines to combat the viral infection are available. Severe acute respiratory syndrome caused by SARS-CoV-2 is treated empirically with antivirals, anti-inflammatory, anticoagulants. The approval of an effective vaccine still takes time. In this state, it may be useful to find new therapeutic solutions from drugs already on the market. Recent hypotheses suggest that the use of AT-1 receptor antagonists (ARB) in combination with neprilisin inhibitors (NEPi) could indirectly provide clinical benefits to patients with SARS-CoV-2 and cardiac involvement. In this article we investigate and describe a possible innovative pharmacological approach for the treatment of the most severe stages of COVID-19 infection.

The Rationale for Angiotensin Receptor Neprilysin Inhibitors in a Multi-Targeted Therapeutic Approach to COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) determines the angiotensin converting enzyme 2 (ACE2) down-regulation and related decrease in angiotensin II degradation. Both these events trigger "cytokine storm" leading to acute lung and cardiovascular injury. A selective therapy for COVID-19 has not yet been identified. Clinical trials with remdesivir gave discordant results. Thus, healthcare systems have focused on "multi-targeted" therapeutic strategies aiming at relieving systemic inflammation and thrombotic complications. No randomized clinical trial has demonstrated the efficacy of renin angiotensin system antagonists in reducing inflammation related to COVID-19. Dexamethasone and tocilizumab showed encouraging data, but their use needs to be further validated. The still-controversial efficacy of these treatments highlighted the importance of organ injury prevention in COVID-19. Neprilysin (NEP) might be an interesting target for this purpose. NEP expression is increased by cytokines on lung fibroblasts surface. NEP activity is elevated in acute respiratory distress syndrome and it is conceivable that it is also high in COVID-19. NEP is implicated in the degradation of natriuretic peptides, bradykinin, substance P, adrenomedullin, and apelin that account for prevention of organ injury. Thus, NEP/angiotensin receptor type 1 (AT1R) inhibitor sacubitril/valsartan (SAC/VAL) may increase levels of these molecules and block AT1Rs required for ACE2 endocytosis in SARS-CoV-2 infection. Moreover, SAC/VAL has a positive impact on acute heart failure that is very frequently observed in deceased COVID-19 patients. The current review aims to summarize actual therapeutic strategies for COVID-19 and to examine the data supporting the potential benefits of SAC/VAL in COVID-19 treatment.

Sacubitril/Valsartan in Advanced Heart Failure With Reduced Ejection Fraction: Rationale and Design of the LIFE Trial.

The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in the PARADIGM-HF study had New York Heart Association (NYHA) functional class IV symptoms. Accordingly, data that informed the use of S/V among patients with advanced HF were limited. The LIFE (LCZ696 in Hospitalized Advanced Heart Failure) study was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial that compared the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HFrEF. The trial planned to randomize 400 patients ≥18 years of age with advanced HF, defined as an EF ≤35%, New York Heart Association functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/ml or N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/ml), and ≥1 objective finding of advanced HF. Following a 3- to 7-day open label run-in period with S/V (24 mg/26 mg twice daily), patients were randomized 1:1 to S/V titrated to 97 mg/103 mg twice daily versus 160 mg of V twice daily. The primary endpoint was the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints included clinical outcomes and safety and tolerability. Because of the COVID-19 pandemic, enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis consists of the first 335 randomized patients whose clinical follow-up examination results were not severely impacted by COVID-19. (Entresto [LCZ696] in Advanced Heart Failure [LIFE STUDY] [HFN-LIFE]; NCT02816736).

[Impact of the COVID-19 pandemic on the management of heart failure outpatient clinics. Lessons during the lockdown restrictions]. / Le ricadute della pandemia COVID-19 sulla gestione dell'Ambulatorio Scompenso. Esperienze e considerazioni operative dopo il lockdown.

BACKGROUND: During the COVID-19 pandemic, non-urgent outpatient activities were temporarily suspended. The aim of this study was to assess the impact of this measure on the management of the heart failure outpatient clinic at our institution. METHODS: We analyzed the clinical outcome of 110 chronic heart failure patients (mean age 73 ± 9 years) whose follow-up visit had been delayed. RESULTS: At their last visit before the lockdown, 80.9% was in NYHA class II, had an ejection fraction of 37 ± 7%, and B-type natriuretic peptide level was moderately elevated (266 ± 138 pg/ml). All patients received loop diuretics, 97.2% beta-blockers, 64.9% an aldosterone antagonist, 60.9% sacubitril/valsartan (S/V), and 72.2% of the remaining patients were on angiotensin-converting enzyme inhibitor or valsartan therapy. Patients were contacted by phone during and at the end of the lockdown period to fix a new appointment and underwent a structured interview to assess their clinical conditions and ongoing therapy and to verify whether they had contracted SARS-CoV-2 infection. Twelve patients (13.2%) contracted COVID-19. None was hospitalized for worsening heart failure or reported defibrillator shocks and none changed autonomously the prescribed therapy. Overall, 75% of patients reported stable or improved general well-being from the last in-person visit, while 25% described subjective worsening due to the social effect of the pandemic. Unchanged body weight and blood pressure values were reported by 86% and 78.4% of patients, respectively. Lower blood pressure values compared to baseline were recorded in 15.2% of patients on conventional renin-angiotensin system inhibition vs 21% of those on S/V, one of whom had to down-titrate S/V for persistent but asymptomatic hypotension; 4 patients up-titrated S/V to 200 mg/day following phone indications. CONCLUSIONS: Cancellation of scheduled follow-up visits during 3 months did not have significant negative effects in a cohort of stable patients with chronic heart failure on optimized medical therapy. Telephone support was effective in keeping connections with the patients during the lockdown, allowing appropriate management and implementation of drug therapy. In particular, patients who received S/V were not affected by delays in scheduled visits, confirming the tolerability and safety of this novel therapy in terms of both clinical and biohumoral parameters.